Drug coating layer

ABSTRACT

Provided are a drug coating layer which has low toxicity and a high intravascular stenosis inhibitory effect, when delivering medical device coated with a drug into the body and medical device using the same. The drug coating layer is a drug coating layer having a morphological form including a plurality of elongated bodies having long axes that each crystal of a water-insoluble drug independently has on a substrate surface, in which the long axes of the elongated bodies are nearly linear in shape, and the long axes of the elongated bodies form an angle in a predetermined range with respect to a substrate plane with which the long axis of the elongated body intersects.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of International Application No. PCT/JP2014/059665 filed on Apr. 1, 2014, and claims priority to Japanese Application No. 2013-076434 filed on Apr. 1, 2013, the entire content of both of which is incorporated herein by reference.

TECHNICAL FIELD

The present disclosure relates to a drug coating layer of water-insoluble drugs, and to a drug coating layer exhibiting a specific crystalline morphological form of the water-insoluble drugs.

BACKGROUND DISCUSSION

In recent years, development of a drug eluting balloon (DEB) in which a balloon catheter is coated with drugs has been actively performed, and it has been reported to be effective in the treatment and prevention of restenosis. The balloon is coated by a coating layer including drugs and excipients, such that when a blood vessel is dilated, the balloon presses against a blood vessel wall, and it delivers the drugs to target tissue.

In recent years, it is found that a morphological form of drugs coated on a balloon surface influences the releasing property and tissue transferability of drugs from the balloon surface in a lesion affected area, and control of a crystalline form or an amorphous of drugs is known to be important.

PTL 1 and PTL 2 disclose a method in which by using annealing with solvent vapor, the morphological form of drugs coated on a balloon surface is changed from the amorphous to the crystalline form. PTL 2 further discloses that the crystalline form of paclitaxel obtained by annealing has a fan-like form and a rod-like form or a needle-like form, and that the rod-like crystalline form has a higher drug transferability in the target tissue compared to the fan-like form.

In addition, PTL 3 discloses that paclitaxel in a crystalline hydrated form is coated, and the crystalline hydrated form has a preferable releasing property and tissue transferability of drugs in the lesion affected area compared to a non-hydrated form and amorphous form.

Thus, PTL 3 discloses that the drug eluting balloon having a crystalline form of paclitaxel exhibits excellent tissue transferability of drugs; however, it does not describe the detailed morphological form of a crystal and an intravascular stenosis inhibitory effect.

In contrast, there is a concern that the drug eluting balloon having a crystalline form of paclitaxel exhibits strong toxicity with respect to target tissue in some cases. Therefore, in the recent development of the drug eluting balloon, it is required that the drug eluting balloon have a suitable balance between efficacy and toxicity, that is, high effect (intravascular stenosis inhibitory effect) and low toxicity. In PTL 1, PTL 2 and PTL 3, the toxicity is not described at all, and a crystalline morphological form of a drug having a suitable balance between efficacy and toxicity is not yet clear.

Based on what has been described above, since it cannot be said that the drug eluting balloon having a coating layer in the related art sufficiently exhibits low toxicity and a high effect on a stenosis inhibition rate when treating a stenosis portion in a blood vessel, a medical device having a suitable balance between efficacy and toxicity is desired.

PTL 1: PCT International Publication No. WO2010/124098

PTL 2: JP-T-2012-533338 PTL 3: JP-T-2012-514510 SUMMARY

The present disclosure can provide a drug coating layer having a morphological form of water-insoluble drugs of which the intravascular stenosis inhibitory effect in a lesion affected area is high, when delivering a medical device coated with a drug into the body and a medical device using the same.

In order to address the described challenge in the art, it has been found that a drug coating layer having a specific crystalline morphological form of a water-insoluble drug has a high intravascular stenosis inhibitory effect in a lesion affected area.

Various aspects are disclosed as follows:

(1) A drug coating layer which has a morphological form including a plurality of elongated bodies with long axes so that each crystal of a water-insoluble drug independently has, on a substrate surface, in which the long axes of the elongated bodies are nearly linear in shape, and the long axes of the elongated bodies form an angle in a predetermined range, preferably an angle in a range of 45° to 135°, with respect to a substrate plane with which the long axis of the elongated body intersects.

(2) The drug coating layer described in (1) in which at least near the distal of the elongated body is hollow.

(3) The drug coating layer described in (1) or (2) in which a cross-sectional shape of the elongated body on a surface perpendicular to the long axis is a polygon.

(4) The drug coating layer in which flatly elongated hair shaped crystals of the water-insoluble drug are randomly laminated on the substrate surface, and in which the long axes of the crystals partly have a portion curved in shape, and crystals having other shapes are not mixed in the same crystal plane.

(5) The drug coating layer described in (4) in which the surface of the crystal of the water-insoluble drug is further covered with an amorphous film.

(6) The drug coating layer including a crystalline morphological form of the water-insoluble drug, crystal particles of the water-insoluble drug which are arranged with regularity on the substrate surface, and excipient particles formed of an excipient which are irregularly arranged between the crystal particles, in which a molecular weight of the excipient is less than a molecular weight of the water-insoluble drug, a ratio occupied by the excipient particles per a predetermined area of the substrate is less than a ratio occupied by the crystal particles, and the excipient particles do not form a matrix.

(7) The drug coating layer described in any one of (1) to (6) in which the water-insoluble drug is rapamycin, paclitaxel, docetaxel, or everolimus.

(8) Medical device having the drug coating layer described in any one of (1) to (7) on the surface of the medical device, which is reduced in diameter to be delivered when delivered into a body, and enlarged in diameter to release a drug from the drug coating layer at an affected part.

(9) A method for delivering a drug having a step of delivering the medical device described in (8) to a lumen, a step of radially dilating a dilatable portion provided in the medical device, and a step in which the drug coating layer which the dilatable portion has is applied to the lumen.

The disclosed embodiments can provide a drug coating layer for drug eluting medical device of which the intravascular stenosis inhibitory effect in a lesion affected area is high, and/or the toxicity is low.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A to 1D are diagrams showing a scanning electron microscopic image (hereinafter, referred to as SEM) of a surface of a drug coating layer prepared in Example 1. FIG. 1A is a SEM image at 2,000 times magnification of crystals observed on a substrate surface of the drug coating layer prepared in Example 1. FIG. 1B is a SEM image at 1,000 times magnification of crystals observed on another portion of a substrate surface prepared in Example 1. FIG. 1C is a SEM image at 400 times magnification of crystals observed on another portion of the substrate surface prepared in Example 1. FIG. 1D is a SEM image at 4,000 times magnification of crystals observed at a cross-section perpendicular to the substrate surface of the drug coating layer prepared in Example 1.

FIG. 2 is a diagram showing a SEM image at 2,000 times magnification of crystals observed on the substrate surface of the drug coating layer prepared in Example 2.

FIG. 3A is a diagram showing a SEM image at 2,000 times magnification of crystals observed on the substrate surface of the drug coating layer prepared in Example 3. FIG. 3B is a SEM image at 4,000 times magnification of crystals observed at a cross-section perpendicular to the substrate surface of the drug coating layer prepared in Example 3.

FIG. 4 is a diagram showing a SEM image at 2,000 times magnification of crystals observed on the substrate surface of the drug coating layer prepared in Example 4.

FIG. 5 is a diagram showing a SEM image at 2,000 times magnification of crystals observed on the substrate surface of the drug coating layer prepared in Example 6.

FIG. 6A is a diagram showing a SEM image at 2,000 times magnification of crystals observed on the substrate surface of the drug coating layer prepared in Example 6. FIG. 6B is a diagram showing a SEM image at 400 times magnification of crystals observed on another portion of the substrate surface of the drug coating layer prepared in Example 6.

FIG. 7 is a diagram showing a SEM image at 2,000 times magnification of crystals observed on the substrate surface of the drug coating layer of a commercially available drug eluting balloon (IN.PACT) manufactured by INVAtec JAPAN in Comparative Example 1.

FIG. 8 is a graph of an intravascular stenosis rate (%) showing an inhibitory effect on an intravascular stenosis in a porcine coronary artery.

DETAILED DESCRIPTION

It has been determined that a drug coating layer having low toxicity in the lesion affected area and a high intravascular stenosis inhibitory effect has a specific crystalline form of a water-insoluble drug when delivering a medical device coated with a drug into the body.

The following crystalline forms are preferably exemplified.

(1) Layer Including Crystalline Morphological Form of Long Hollow Object

The layer having a morphological form including crystals of a long hollow object is a drug coating layer in which a plurality of elongated bodies having long axes formed of crystals of the water-insoluble drug are present in a brush shape on the substrate surface. The plurality of elongated bodies are circumferentially arranged in a brush shape on the substrate surface. Each of the elongated bodies is independently present, has a length, and has one end (proximal) of the elongated body fixed to the substrate surface. The elongated bodies do not form a composite structure with adjacent elongated bodies, and are not connected with each other. The long axis of the crystal is nearly linear in shape. The elongated body forms a predetermined angle with respect to the substrate plane which the long axis intersects. The predetermined angle is in the range of 45° to 135°. The predetermined angle is preferably in a range of 70° to 110°, and more preferably in a range of 80° to 100°. It is more preferable that the long axis of the elongated body form an angle of nearly 90° with respect to the substrate plane. At least near the distal, the elongated body is hollow. The cross section of the elongated body is hollow in a surface perpendicular to the long axis of the elongated body. The cross section of the hollow elongated body in a surface perpendicular to the long axis is a polygon. Examples of the polygon include a tetragon, a pentagon, and a hexagon. Accordingly, the elongated body has the distal (or distal surface) and the proximal (or proximal surface), and a side surface between the distal (or distal surface) and the proximal (or proximal surface) formed as a long polyhedron which is constituted with a plurality of planes. The crystalline morphological form constitutes the whole of or at least a part of a plane on the substrate surface. For example, the layer including the crystalline morphological form of the long hollow object is a layer having the crystalline morphological form shown in SEM images of FIGS. 1 to 4.

For example, characteristics of the layer having the morphological form including the crystals of a long hollow object are as follows.

1) A plurality of elongated bodies (rod) have independent long axes, and the elongated body is hollow. The elongated body has a rod shape.

2) The elongated bodies have long axes, and in many cases, is a polyhedron, in which the cross section of the elongated body in a surface perpendicular to the long axis is polygonal. Equal to or greater than 50% by volume of the elongated body crystal is a long polyhedron. The side surface of the polyhedron is mainly a tetrahedron. In some cases, the long polyhedron has a plurality of surfaces (grooves) which are formed of a reentrant angle in which a vertex is extended in a long axis direction. Herein, the reentrant angle means that at least one of the interior angles of the polygon of a cross section of the elongated body in a plane perpendicular to the long axis is greater than an angle of 180°.

3) In many cases, the elongated body having a long axis is a long polyhedron. When viewed in a cross section perpendicular to the long axis, the cross section is polygonal, and is observed as a tetragon, a pentagon, or a hexagon.

4) A plurality of elongated bodies having independent long axes stand in a row with an angle in a predetermined range, preferably in a range of 45° to 135°, with respect to the substrate surface, that is, the plurality of elongated bodies having independent long axes nearly uniformly stand like a forest on the substrate surface. The region where the elongated bodies stand like a forest is nearly uniformly formed extended in the circumferential direction and the axial direction on the substrate surface. Each angle with respect to the substrate surface of each independent elongated body may be different or the same in the predetermined range.

5) One end (proximal) of the each elongated body having independent long axis is fixed to the substrate surface.

6) In some cases, in a portion near the substrate surface, particle-like, short rod-like or short curve-like crystals are laminated. The elongated body which directly or indirectly has a long axis on the substrate surface is present. Therefore, there is a case where the elongated bodies having long axes on the laminate stand like a forest.

7) A length in the axial direction of the elongated body having a long axis is preferably 5 μM to 20 μm, more preferably 9 μm to 11 μm, and still more preferably about 10 μm. A diameter of the elongated body having a long axis is preferably 0.01 μm to 5 μm, more preferably 0.05 μm to 4 μm, and still more preferably 0.1 μm to 3 μm.

8) Other morphological forms (for example, a plate shaped morphological form which is amorphous) are not mixed on the surface of the layer including the crystalline morphological form of a long hollow object. More typically, the crystalline morphological forms 1) to 7) are equal to or greater than 50% by volume, and more preferably equal to or greater than 70% by volume. More preferably, almost all form the crystalline morphological form of 7).

9) In the crystalline morphological form of the long hollow object, it is possible that other compounds are present in the drug coating layer including water-insoluble drug constituting crystals. In this case, the compounds are present in a state of being distributed in the space between crystals (elongated body) of a plurality of the water-insoluble drugs which stand like a forest on a balloon substrate surface. In the ratio of the materials constituting the drug coating layer, the crystals of the water-insoluble drugs occupy a much greater volume than other compounds in this case.

10) In the crystalline morphological form of long hollow object, the water-insoluble drugs constituting crystals are present on the balloon substrate surface. In the drug coating layer of the balloon substrate surface having the water-insoluble drugs constituting crystals, a matrix by the excipient is not formed. Therefore, the water-insoluble drugs constituting crystals are not attached to the matrix material. The water-insoluble drugs constituting crystals are also not embedded in the matrix material.

11) In the crystalline morphological form of long hollow object, the drug coating layer may include crystal particles of the water-insoluble drugs which are arranged with regularity on the substrate surface, and excipient particles formed of an excipient which are irregularly arranged between the crystal particles. In this case, a molecular weight of the excipient is less than a molecular weight of the water-insoluble drugs. Therefore, the ratio that the excipient particles occupy per a predetermined area, of the substrate is smaller than the ratio that crystal particles occupy, and the excipient particles do not form a matrix. Here, the crystal particles of the water-insoluble drugs may be one of the elongated body, and since the excipient particles are present in a state of being much smaller than the crystal particles of the water-insoluble drugs, and are dispersed among the crystal particles of the water-insoluble drugs, there is a case where the excipient particles are not observed in the SEM image.

The flat hair shaped crystalline morphological form to be described below occupies at least a part of the drug coating layer, equal to or greater than 50% by volume, equal to or greater than 80% by volume, (equal to or greater than 50% by volume as a crystal, more and preferably equal to or greater than 70% by volume), and still more preferably nearly 100% by volume. In a case of occupying nearly 100% by volume, it is in a state that a plurality of crystalline morphological forms are not being mixed, and only a single crystalline morphological form is present.

(2) Layer Including Flat Hair Shaped Crystalline Morphological Form

The layer including a flat hair shaped crystalline morphological form is a drug coating layer in which crystals of a flatly elongated hair shaped crystals of the water-insoluble drug are randomly laminated on the substrate surface, and in which the long axes of the crystals partly have a portion curved in shape, and crystals having other morphological forms are not mixed in the same crystal plane. In a case where an amorphous layer and a crystal layer are present, “not the same crystal plane” means that the amorphous film is present on the crystal layer. For example, the layer including the flat hair shaped crystalline morphological form is a layer having the crystalline form of Example 6 shown in FIG. 6A.

For example, characteristics of the layer including the flat hair shaped crystalline morphological form are as follows.

1) A hair shaped crystal having a long axis has a shape flatly jointed in a plurality of width directions, does not have hollow portion, and has a tapered shape.

2) The joint shape of the hair shaped crystal is randomly laminated on the substrate surface. The long axis is present in a state reclined along the substrate surface.

3) The long axis of the crystals partly have a portion curved in shape.

4) A length in the long-axis direction of the hair shaped crystal is preferably 10 μm to 100 μm, more preferably about 20 μm, and is longer than a length of the crystalline morphological form of a long hollow object in many cases.

(3) Layer including morphological form in which an amorphous film is present on the surface of the flat hair shaped crystal.

The layer is a drug coating layer in which the surface of the flat hair shaped crystal is covered with an amorphous film. The layer including the morphological form in which an amorphous film is present on the surface of the flat hair shaped crystal, in which a layer of an amorphous film is present on the flat hair shaped crystal, is formed of two layers of the crystal and the amorphous film. For example, the layer including the morphological form in which an amorphous film is present on the surface of the flat hair shaped crystal is a layer having the crystalline form of Example 6 shown in FIG. 6B.

Specifically, on a certain plane (plane in which crystal/amorphous film are present), a certain crystalline form is at least partly present, or a certain crystalline form is present by equal to or greater than 50% by volume, or equal to or greater than 80% by volume, (equal to or greater than 50% by volume as a crystal, and more preferably equal to or greater than 70% by volume), still more preferably a plurality of crystalline forms are not mixed, and an amorphous film may be present on the outside of a certain plane.

The crystal layers of the morphological form of the long hollow object, the morphological form of the flat hair shaped crystal, and the morphological form in which an amorphous film is present on the surface of the flat hair shaped crystal have low toxicity and a high intravascular stenosis inhibitory effect when delivering a medical device in which the substrate surface is coated with a drug into the body as a drug coating layer. While not limiting, it is believed that the solubility and retentivity in tissue after a drug having a certain crystalline form is transferred into the tissue is affected. For example, in a case of an amorphous form, since solubility is high, even when the drug is transferred into a tissue, it immediately flows into the blood stream. Therefore, the retentivity in the tissue is low, and thus an excellent stenosis inhibitory effect cannot be obtained. On the other hand, the water-insoluble drug having a specific crystalline form as disclosed herein effectively acts to inhibit the stenosis since when the drug is transferred into a tissue, one unit of the crystal becomes small, and therefore, the permeability into the tissue and the solubility thereof are excellent. In addition, it is considered that since the quantity of the drug remaining in the tissue as a large mass is small, the toxicity is low.

In particular, the layer including the crystalline morphological form of a long hollow object is a plurality of nearly uniform elongated bodies having long axes, and a morphological form which substantially uniformly stands in a row with regularity on the substrate surface. Therefore, the crystals transferred into a tissue have a small size (length in long-axis direction) of about 10 μm. For this reason, the drug uniformly acts on the lesion affected area, and tissue penetrability is increased. Further, it is considered that since the size of the crystals transferred is small, an excessive amount of the drug does not remain in the affected area for an excessive amount of time, and the toxicity is not expressed, and a high stenosis inhibitory effect can be exhibited.

The water-insoluble drug means a drug that is insoluble or poorly soluble in water, and specifically, solubility in water is less than 5 mg/mL at pH 5 to 8. The solubility may be less than 1 mg/mL, and further, may be less than 0.1 mg/mL. The water-insoluble drug includes a fat-soluble drug.

Examples of some preferable water-insoluble drugs include immunosuppressive drugs such as cyclosporines including cyclosporine, immunoactive drugs such as rapamycin, anticancer drugs such as paclitaxel, an antiviral drug or an antibacterial drug, an antineoplastic tissue drug, an analgesic drug and an antiinflammatory drug, an antibiotic drug, an antiepileptic drug, an anxiolytic drug, an antiparalysis drug, an antagonist, a neuron blocking drug, an anticholinergic drug and a cholinergic drug, an antimuscarinic drug and a muscarinic drug, an antiadrenergic drug, an antiarrhythmic drug, an antihypertensive drug, a hormone drug, and a nutritional supplement.

The water-insoluble drug is preferably at least one selected from a group formed of rapamycin, paclitaxel, docetaxel, and everolimus. In the specification, rapamycin, paclitaxel, docetaxel, and everolimus include analogs and/or derivatives thereof as long as these have similar drug efficacy. For example, the paclitaxel is an analogue of the docetaxel. The rapamycin is an analogue of the everolimus. Among these, the paclitaxel is more preferable.

The water-insoluble drug may further include an excipient. The excipient is not limited as long as it is pharmaceutically acceptable, and examples thereof include water-soluble polymers, sugars, contrast agents, citric acid esters, amino acid esters, glycerol esters of short-chain monocarboxylic acid, pharmaceutically acceptable salts, surfactants, and the like.

A coating solution is prepared by dissolving a water-insoluble drug in a solvent. The coating solution is coated on a dilated balloon such that the solvent of the coating solution is slowly volatilized. Preferably, a drug is discharged from the distal opening portion of a dispensing tube while generally bring a side surface of the distal of the dispensing tube where a drug is discharged into contact with a surface of a balloon catheter. The balloon catheter rotates in an opposite direction (reverse direction) to the drug discharging direction about a long axis. Thereafter, the balloon after coating was dried, thereby preparing a drug coating layer including the crystal layer.

Preferred condition for coating Balloon with coating solution

Rotational speed of Balloon 10 to 200 rpm preferably 30 to 180 rpm more preferably 50 to 150 rpm Mobile speed of Dispenser 0.01 to 2 mm/sec preferably 0.03 to 1.5 mm/sec more preferably 0.05 to 1.0 mm/sec Diameter of Balloon 1 to 10 mm preferably 2 to 7 mm Drug discharging rate 0.01 to 1.5 μL/sec Preferably 0.01 to 1.0 μL/sec More preferably 0.03 to 0.8 μL/sec

As the solvent used, which is not particularly limited, tetrahydrofuran, ethanol, glycerin (also referred to as glycerol or propane-1,2,3-triol), acetone, methanol, dichloromethane, hexane, ethyl acetate, and water are exemplified. Among these, a mixed solvent in which some from among tetrahydrofuran, ethanol, acetone, and water are mixed is preferable.

A medical device has the drug coating layer directly or through the pretreatment layer such as a primer layer on the surface of the substrate. The drug coating layer contains a drug at a density of 0.1 μg/mm² to 10 μg/mm², preferably at a density of 0.5 μg/mm² to 5 μg/mm², more preferably at a density of 0.5 μg/mm² to 3.5 μg/mm², even more preferably at a density of 1.0 μg/mm² to 3.0 μg/mm², but it is not particularly limited thereto.

The shape and materials of the substrate are not particularly limited. Metals and resins may be used as materials. The material may be any one of a film, a plate, a wire rod, and an irregular shaped material, and may be a particulate.

The medical device used is not limited. Any medical device that is transplantable or insertable may be used. The medical device which is long, delivered in the non-dilated state with a reduced diameter in a body cavity such as blood, and enlarged in diameter in a circumferential direction at a part such as a blood vessel or a tissue to release a drug from the drug coating layer is preferable. Therefore, the medical device that is reduced in diameter to be delivered, and enlarged in diameter to be applied to an affected area is a medical device having a dilation portion. The drug coating layer is provided on at least a part of the surface of the dilation portion. That is, the drug is coated on, at least, the outer surface of the dilation portion.

The materials of the dilation portion of the medical device preferably have a certain degree of flexibility, and at certain degree of hardness such that the drug is released from the drug coating layer on the surface by being dilated when the medical device reaches a blood vessel or a tissue. Specifically, the medical device is constituted of a metal or a resin, and the surface of the dilation portion on which the drug coating layer is provided is preferably constituted of a resin. The resin constituting the surface of the dilation portion is not particularly limited, and preferable examples thereof include polyamides. That is, at least a part of the surface of the dilation portion of the medical device which is coated with a drug is a polyamide. Examples of the polyamide, which is not particularly limited as long as it is a polymer having an amide bond, include homopolymers such as polytetramethylene adipamide (Nylon 46), polycaprolactam (Nylon 6), polyhexamethylene adipamide (Nylon 66), polyhexamethylene sebacamide (Nylon 610), polyhexamethylene dodecamide (Nylon 612), polyundecanolactam (Nylon 11), polydodecanolactam (Nylon 12), copolymers such as a caprolactam/lauryl lactam copolymer (Nylon 6/12), a caprolactam/aminoundecanoic acid copolymer (Nylon 6/11), a caprolactam/ω-aminononanoic acid copolymer (Nylon 6/9), a caprolactam/hexamethylene diammonium adipate copolymer (Nylon 6/66), and aromatic polyamides such as a copolymer of adipic acid and m-xylene diamine, or a copolymer of hexamethylene diamine and m,p-phthalic acid. Further, a polyamide elastomer which is a block copolymer in which Nylon 6, Nylon 66, Nylon 11, or Nylon 12 is a hard segment, and a polyalkylene glycol, a polyether, or an aliphatic polyester is a soft segment can be used as a substrate material for the medical device. The polyamides may be solely used, or two or more kinds thereof may be jointly used.

Specifically, as the medical device having the dilation portion, a long catheter having a dilation portion (stent) or a dilation portion (balloon) is exemplified.

In one preferred aspect, the drug coating layer is formed on the surface of the balloon at the time of dilating, and the balloon is wrapped (folded), inserted into a blood vessel, a body cavity or the like, delivered to tissue or affected area, and enlarged in diameter in the affected area, and then, the drug is released.

Hereinafter, illustrative examples and the comparative examples will be described, but, the present disclosure is not limited to the examples. Manufacture or preparation of drug eluting balloon, or preparation of non-drug coated balloon

Example 1 (1) Preparation of Coating Solution 1

L-serine ethyl ester hydrochloride (CAS No. 26348-61-8) (56 mg) and paclitaxel (CAS No. 33069-62-4) (134.4 mg) were weighed. Absolute ethanol (1.2 mL), tetrahydrofuran (1.6 mL), and RO (reverse osmosis) membrane-treated water (hereinafter, referred to as RO water) (0.4 mL) were respectively added thereto and dissolved, thereby preparing a coating solution 1.

(2) Drug Coating on Balloon

A balloon catheter (manufactured by Terumo Corp., the material of the balloon (dilation portion) is a nylon elastomer) having a size of a diameter 3.0 mm×a length 20 mm (dilation portion) when dilated was prepared. The coating solution 1 was coated on the dilated balloon such that the solvent of the coating solution is slowly volatilized to make the amount of paclitaxel be about 3 μg/mm². Preferably, the drug was discharged from the distal opening portion of a dispensing tube while generally bring a side surface of the distal of the dispensing tube where the drug is discharged into contact with a surface of the balloon catheter. The balloon catheter was rotated in an opposite direction (reverse direction) to the drug discharging direction about a long axis. Mobile speed of the balloon catheter of the dispensing tube in an axis direction and rotational speed of the balloon were adjusted, and when balloon started to rotate, the drug was discharged at 0.053 μL/sec to be coated on the balloon. Thereafter, the balloon coating was dried, thereby making a drug eluting balloon.

Example 2 (1) Preparation of Coating Solution 2

L-serine ethyl ester hydrochloride (70 mg) and paclitaxel (180 mg) were weighed. Absolute ethanol (1.5 mL), acetone (2.0 mL), tetrahydrofuran (0.5 mL), and RO water (1 mL) were added thereto respectively and dissolved, thereby preparing a coating solution 2.

(2) Drug Coating on Balloon

A balloon catheter (manufactured by Terumo Corp., the material of the balloon (dilation portion) is a nylon elastomer) having a size of a diameter 3.0 mm×a length 20 mm (dilation portion) when dilated was prepared. The coating solution 2 was coated on the dilated balloon such that the solvent of the coating solution is slowly volatilized to make the amount of paclitaxel be about 3 μg/mm². Specifically, a drug was coated on the balloon with the same method described in Example 1 except that the drug was discharged at 0.088 μL/sec. Thereafter, the balloon coating was dried, thereby making a drug eluting balloon.

Example 3 (1) Preparation of Coating Solution 3

L-serine ethyl ester hydrochloride (70 mg) and paclitaxel (168 mg) were weighed. Absolute ethanol (1.5 mL), tetrahydrofuran (1.5 mL), and RO water (1 mL) were added thereto respectively and dissolved, thereby preparing a coating solution 3.

(2) Drug Coating on Balloon

A balloon catheter (manufactured by Terumo Corp., the material of the balloon (dilation portion) is a nylon elastomer) having a size of a diameter 3.0 mm×a length 20 mm (dilation portion) when dilated was prepared. The coating solution 3 was coated on the dilated balloon such that the solvent of the coating solution is slowly volatilized to make the amount of paclitaxel be about 3 μg/mm². Specifically, a drug was coated on the balloon with the same method described in Example 1 except that the drug was discharged at 0.101 μL/sec. Thereafter, the balloon coating was dried, thereby making a drug eluting balloon.

Example 4 (1) Preparation of Coating Solution 4

L-serine ethyl ester hydrochloride (70 mg) and paclitaxel (180 mg) were weighed. Absolute ethanol (1.75 mL), tetrahydrofuran (1.5 mL), and RO water (0.75 mL) were added thereto respectively and dissolved, thereby preparing a coating solution 4.

(2) Drug Coating on Balloon

A balloon catheter (manufactured by Terumo Corp., the material of the balloon (dilation portion) is a nylon elastomer) having a size of a diameter 3.0 mm×a length 20 mm (dilation portion) when dilated was prepared. The coating solution 4 was coated on the dilated balloon such that the solvent of the coating solution is slowly volatilized to make the amount of paclitaxel be about 3 μg/mm². Specifically, a drug was coated on the balloon with the same method described in Example 1 except that the drug was discharged at 0.092 μL/sec. Thereafter, the balloon coating was dried, thereby making a drug eluting balloon.

Example 5 (1) Preparation of Coating Solution 5

L-aspartic acid dimethyl ester hydrochloride (CAS No. 32213-95-9) (37.8 mg) and paclitaxel (81 mg) were weighed. Absolute ethanol (0.75 mL), tetrahydrofuran (0.96 mL), and RO water (0.27 mL) were added thereto respectively and dissolved, thereby preparing a coating solution 5.

(2) Drug Coating on Balloon

A balloon catheter (manufactured by Terumo Corp., the material of the balloon (dilation portion) is a nylon elastomer) having a size of a diameter 3.0 mm×a length 20 mm (dilation portion) when dilated was prepared. The coating solution 5 was coated on the dilated balloon such that the solvent of the coating solution is slowly volatilized to make the amount of paclitaxel be about 3 μg/mm². Specifically, a drug was coated on the balloon with the same method described in Example 1 except that the drug was discharged at 0.055 μL/sec. Thereafter, the balloon coating was dried, thereby making a drug eluting balloon.

Example 6 (1) Preparation of Coating Solution 6

L-serine ethyl ester hydrochloride (56 mg) and paclitaxel (134.4 mg) were weighed. Absolute ethanol (0.4 mL), tetrahydrofuran (2.4 mL), and RO water (0.4 mL) were added thereto respectively and dissolved, thereby preparing a coating solution 6.

(2) Drug Coating on Balloon

A balloon catheter (manufactured by Terumo Corp., the material of the balloon (dilation portion) is a nylon elastomer) having a size of a diameter 3.0 mm×a length 20 mm (dilation portion) when dilated was prepared. The coating solution 6 was coated on the dilated balloon such that the solvent of the coating solution is slowly volatilized to make the amount of paclitaxel be about 3 μg/mm². Specifically, a drug was coated on the balloon with the same method described in Example 1 except that the drug was discharged at 0.053 μL/sec. Thereafter, the balloon after coating was dried, thereby making a drug eluting balloon.

Comparative Example 1

IN.PACT (manufactured by INVAtec JAPAN) which is a commercially available balloon catheter was prepared. The balloon in Comparative Example 1 is a drug eluting balloon of which the surface is coated with paclitaxel.

Comparative Example 2

A balloon catheter (manufactured by Terumo Corp., the material of the balloon (dilation portion) is a nylon elastomer) having a size of a diameter 3.0 mm×a length 20 mm (dilation portion) when dilated was prepared. The balloon in Comparative Example 2 is a non-drug coated balloon of which the surface is not coated with a drug.

Measurement of Amount of Paclitaxel Coated on Balloon

For the drug eluting balloon in Examples 1 to 6, the amount of paclitaxel coated on the balloon was measured according to the following procedure.

1. Method

After the prepared drug eluting balloon was immersed in a methanol solution, it was shaken with a shaking apparatus for 10 minutes, and then, paclitaxel coated on the balloon was extracted. The absorbance at 227 nm of the methanol solution by which paclitaxel was extracted was measured by high performance liquid chromatography using an ultraviolet-visible spectrophotometer, and the amount of paclitaxel per balloon ([μg/balloon]) was determined. In addition, the amount of paclitaxel per unit area of balloon ([μg/mm²]) was calculated from the amount of obtained paclitaxel and the balloon surface area.

2. Result

Table 1 shows the obtained results. In Table 1, “Balloon surface area” represents a surface area (unit: mm²) when the balloon is dilated, “per each balloon” in “Amount of PTX on a balloon” represents the amount of paclitaxel per one balloon (unit: μg/balloon), and “per unit area” in “Amount of PTX on a balloon” represents the amount of paclitaxel per surface area 1 mm² of the balloon (unit: μg/mm²), respectively.

As shown in Table 1, the amount of paclitaxel coated on the balloon in all of Examples 1 to 6 is about 3 μg/mm², and it was possible to coat the target amount of paclitaxel on a balloon surface.

TABLE 1 Examples/ Coating Amount of PTX on a balloon Comparative solution per each per unit area Examples No. [μg/balloon] [μg/mm²] 1 Coating solution 1 588.9 3.1 2 Coating solution 2 665.5 3.5 3 Coating solution 3 652.6 3.5 4 Coating solution 4 661.3 3.5 5 Coating solution 5 653.3 3.5 6 Coating solution 6 560.2 3.0 [Observation of drug coating layer of drug eluting balloon by scanning electron microscope (SEM)]

1. Method

The drug eluting balloons in Examples 1 to 5 (FIGS. 1 to 5) and Example 6 (FIG. 6) were dried, and after the dried drug eluting balloons were cut to an appropriate size, these were placed on a support, and platinum deposition was performed thereon. In addition, in the same manner, after a commercially available drug eluting balloon (IN.PACT) manufactured by INVAtec JAPAN in Comparative Example 1 also was cut to an appropriate size, it was placed on a support, and platinum deposition was performed thereon. The surface and the inside of the drug coating layers of these platinum deposited samples were observed by a scanning electron microscope (SEM).

2. Result

In the drug coating layers in Examples, crystal layers having a morphological form of a long hollow object, a morphological form of a flat hair shaped crystals, and a morphological form in which an amorphous film is present on the surface of the flat hair shaped crystals were observed.

SEM images shown in FIGS. 1 to 5 were obtained. FIGS. 1 to 4 which are SEM images of Examples 1 to 4 show a layer, including the morphological form of a long hollow object, and it was made clear that uniform paclitaxel crystals of the long hollow objects having a length of about 10 μm are uniformly formed on the balloon surface. These paclitaxel crystals of the long hollow objects have long axes, and the elongated bodies (about 10 μm) having the long axes were formed so as to be in a direction nearly perpendicular to the balloon surface. The diameter of an elongated body was about 2 μm. In addition, the cross section of the elongated body in a surface perpendicular to the long axis was a polygon. The polygon was, for example, a polygon of a tetragon. Further, these nearly uniform long hollow objects of paclitaxel were uniformly and densely (at the same density) formed on the entire surface of the balloon in the same morphological form (structure and shape).

On the other hand, SEM images of FIG. 6A and FIG. 6B in Example 6 show a layer including a morphological form of a flat hair shaped crystals and a morphological form in which an amorphous film is present on the surface of the flat hair shaped crystals, which were paclitaxel crystals of a flatly elongated hair shaped form. Many of these crystals have a comparatively large size equal to or greater than 20 μm, and the long axes are present in a state reclined along the balloon surface (FIG. 6A). Further, as shown in FIG. 6B, a region in which the upper portion of a layer including a morphological form of a flat hair shaped crystals is covered with an amorphous film was present. In the region, the layer including a morphological form in which a layer of an amorphous film is present on the flat crystal structure, two layers are formed of the crystals and the amorphous film, and an amorphous film is present on the surface of the flat hair shaped crystals is shown.

FIG. 6 in Comparative Example 1 is a SEM image of the drug coating layer of a commercially available drug eluting balloon (IN.PACT) manufactured by INVAtec JAPAN. In this image, amorphous and crystal were mixed in the same plane. It was observed that most of them were nearly amorphous, and needle-like crystals were partly mixed in the same plane.

[Intravascular Stenosis Inhibitory Effect in a Pig Coronary Artery and Effect on Blood Vessel Remodeling]

For Examples 1 and 6, Comparative Example 1 (C1: commercially available balloon), and Comparative Example 2 (C2: non-drug coated balloon), the intravascular stenosis inhibitory effect in a porcine coronary artery and an effect on blood vessel remodeling were evaluated in accordance with the following procedure.

1. Method

(1) A guiding catheter with a guide wire was inserted by an 8Fr sheath, and guided to the left and right coronary artery opening portion under X-ray fluoroscopy.

(2) Angiography of each coronary artery was performed (coronary artery: left anterior descending coronary artery (LAD), right coronary artery (RCA), and left circumflex coronary artery (LCX)), and a diameter of coronary artery obtained by angiography was measured by a QCA software.

(3) A site in which a diameter of a stent is 1.2 times, and a diameter of the drug eluting balloon is 1.3 times with respect to a diameter of a blood vessel was selected, and work after stent placement was performed.

(4) After being extended for 30 seconds such that BMS (bare metal stent) stent (stent diameter 3 mm×length 15 mm) in the coronary artery selected is 1.2 times, a balloon catheter for the stent placement was removed. At the stent placement site, after the drug eluting balloon (balloon diameter 3 mm×length 20 mm) having the drug coating layer prepared in Examples 1 and 6 and Comparative Examples 1 and 2 was dilated for 1 minute so as to be 1.3 times with respect to the diameter of a blood vessel, the balloon catheter was removed.

(5) After the drug eluting balloon was dilated, the guiding catheter and the sheath were removed. After a central side of a carotid artery was ligated, a gap of exfoliated muscles of an incision opening of cervical region was sutured with a suture, and the skin was sutured by a surgical stapler.

(6) 28 days after the balloon dilatation, autopsy was performed.

Calculation Method of Intravascular Stenosis Rate

An intravascular stenosis rate was calculated in accordance with the following procedure. Blood vessel images were taken by a Leica microscope and a pathology imaging system. By these images, internal area of an external elastic lamina area, internal elastic lamina area, internal area of lumen, internal area of stent were measured.

Area stenosis rate (%) was calculated from “area stenosis rate=(neointimal area/internal elastic lamina area)×100”.

Calculation Method of a Fibrin Content, Fibrin Content Score

Evaluation of a fibrin content was performed in all circumferences of blood vessel according to the method of Suzuki et al. (NPL 1). NPL 1: Suzuki Y., et. al Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001; 1188-93

The fibrin content score is graded as follows. Score 1: Fibrin localized in a blood vessel was observed, or fibrin is moderately deposited in a region less than 25% of all circumferences of blood vessel observable near a strut of the stent. Score 2: Fibrin is moderately deposited in a region greater than 25% of all circumferences of blood vessel observable, or fibrin is heavily deposited in a region less than 25% of all circumferences of blood vessel observable between the struts and the proximity of the strut. Score 3: Fibrin is severely deposited in a region greater than 25% of all circumferences of blood vessel observable.

In addition, all the scores were obtained by calculating the average value of the three locations, that is, a proximal location, a middle location, and a distal location of the stent placement sites for each blood vessel.

Endothelialization Score Calculation Method, Endothelialization Score

The content of an endothelialization score is as follows. Score 1: Up to 25% of all circumferences of vascular lumen observable is covered with endothelial cells. Score 2: 25% to 75% of all circumferences of vascular lumen observable is covered with endothelial cells. Score 3: Equal to or greater than 75% of all circumferences of vascular lumen observable is covered with endothelial cells.

In addition, all the scores were calculated as an average value of three locations, that is, a proximal, a middle and a distal location to the stent placement site, for each blood vessel.

2. Results for Intravascular Stenosis Inhibitory Effect in a Porcine Coronary Artery

An intravascular stenosis rate was calculated according to the above-described procedure. Table 2 shows the obtained results. In Table 2, 1 and 6 in a column of Examples/Comparative Examples are Examples, and C1 to C2 are Comparative Examples.

In addition, FIG. 8 is a graph showing the blood vessel stenosis rate of Examples 1 and 6, and of Comparative Examples C1 to C2 for the intravascular stenosis inhibitory effect in porcine coronary arteries. In FIG. 8, the horizontal axis represents Examples or Comparative Examples, the numbers 1 and 6 mean Examples 1 and 6, respectively, and the numbers with letters, that is, C1 and C2 mean Comparative Example 1 (C1) and Comparative Example 2 (C2), respectively. In addition, the vertical axis represents the area stenosis rate (unit: %) of a blood vessel.

In Comparative Example 2 (C2), the area stenosis rate of a blood vessel treated with the non-drug coated balloon as a non-drug treated control was 38.9%. The area stenosis rate of a blood vessel treated with the drug eluting balloon in Example 6 was 20.6%, and a significant stenosis inhibitory effect was confirmed as compared to the non-drug treated control. On the other hand, the area stenosis rate of a blood vessel treated with the commercially available drug eluting balloon (IN.PACT) in Comparative Example 1 was 30.4%, and it was found that the area stenosis rate tends to be decreased as compared to the non-drug coated balloon; however, it was estimated that there is sufficient room for improvement in the effect.

In contrast, the area stenosis rate of a blood vessel treated with the drug eluting balloon of Example 1 was 16.8%, and a significant stenosis inhibitory effect was observed as compared to the non-drug treated control and the IN.PACT of Comparative Example 1 (C1). In addition, it showed a stronger effect than in Example 6, and the most excellent stenosis inhibitory effect was obtained.

Based on what has been described above, it was made clear that the drug eluting balloon of the drug coating layer having the paclitaxel crystalline morphological form of Examples 1 and 6 exhibits a significantly stronger stenosis inhibitory effect than the commercially available drug eluting balloon.

TABLE 2 Examples/ Comparative Examples Stenosis rate [%] S.D. 1 16.8 3.9 6 20.6 5.9 C1 30.4 10.3 C2 38.9 13.8 3. Results for Blood Vessel Remodeling after Stent Placement in a Porcine Coronary Artery (Toxicity)

As the effect (toxicity) on the blood vessel remodeling after the stent placement in a porcine coronary artery, the fibrin content score and endothelialization score were observed. The results are shown in Table 3. With respect to the fibrin content score, the larger the number of the score is, the larger the fibrin content is, which is not preferable. On the other hand, with respect to the endothelialization score, the smaller the number of the score is, the less blood vessel is covered with the endothelial cells, which is not preferable. In Table 3, 1 and 6 in a column of Examples/Comparative Examples are Examples, and C1 and C2 are Comparative Examples.

The fibrin content score and endothelialization score of a blood vessel treated with the non-drug coated balloon as a non-drug treated control in Comparative Example 2 (C2) do not have an influence on the vascular remodeling since there is no effect (toxicity) by drugs, and the scores were 1.00±0.00 and 3.00±0.00, respectively.

The fibrin content score and endothelialization score in Comparative Example 1 (C1) were 1.27±0.15 and 2.80±0.11, respectively, and the scores were nearly the same as those in the non-drug coated balloon. It is estimated that effect (toxicity) on the vascular remodeling is also small since the stenosis inhibition effect by drugs is small.

On the other hand, the fibrin content score and endothelialization score of a blood vessel treated with the drug eluting balloon of Example 6 were 2.61±0.16 and 1.78±0.17, respectively, and it was suggested that the effect on the vascular remodeling was great as compared to those of Comparative Example 1 (C1) and Comparative Example 2 (C2). It is considered that this is because the stenosis inhibition effect is stronger than in Comparative Example 1 (C1) and Comparative Example 2 (C2).

In contrast, the fibrin content score and endothelialization score of a blood vessel treated with the drug eluting balloon of Example 1 were 1.53±0.17 and 2.87±0.09, respectively, and it was made clear that the effect (toxicity) on the vascular remodeling was the same as that of the commercially available product in Comparative Example 1 (C1), and in spite that high stenosis inhibition effect was obtained, the toxicity was extremely low.

Based on what has been described above, the drug eluting balloon of the drug coating layer having the paclitaxel crystalline morphological form of Example 6 has a significantly stronger stenosis inhibition effect. Further, it was made clear that the drug eluting balloon of the drug coating layer having the paclitaxel crystalline morphological form of Example 1 has a significantly stronger stenosis inhibition effect, hardly exhibits the effect (toxicity) on the vascular remodeling, and thus, it is an excellent drug eluting balloon in terms of effectiveness and side effects (toxicity).

TABLE 3 Examples/ Comparative Examples Fibrin content score Endothelialization score 1 1.53 ± 0.17 2.87 ± 0.09 6 2.61 ± 0.16 1.78 ± 0.17 C1 1.27 ± 0.15 2.80 ± 0.11 C2 1.00 ± 0.00 3.00 ± 0.00

The detailed description above describes a drug coating layer, medical device having the drug coating layer and method for delivering a drug. The invention is not limited, however, to the precise embodiment and variations described. Various changes, modifications and equivalents can be effected by one skilled in the art without departing from the spirit and scope of the invention as defined in the accompanying claims. It is expressly intended that all such changes, modifications and equivalents which fall within the scope of the claims are embraced by the claims. 

What is claimed is:
 1. A drug coating layer having a morphological form including a plurality of elongated bodies of independent crystals of a water-insoluble drug having longitudinal axes on a substrate surface, wherein the longitudinal axes of the elongated bodies are generally linear in shape, and the longitudinal axes of the elongated bodies form an angle in a predetermined range with respect to a substrate plane with which the long axis of the elongated body intersects.
 2. The drug coating layer according to claim 1, wherein at least a vicinity of the distal of the elongated body is hollow.
 3. The drug coating layer according to claim 1, wherein a cross-sectional shape of the elongated body on a surface perpendicular to the longitudinal axis is a polygon.
 4. The drug coating layer according to claim 3, wherein the polygon is selected from the group consisting of a tetrahedron, a pentagon and a hexagon.
 5. The drug coating layer according to claim 4, wherein the polygon is a tetrahedron.
 6. The drug coating layer according to claim 1, wherein the angle is in the range of 45 to 135° with respect to the substrate plane.
 7. The drug coating layer according to claim 6, wherein the angle is in the range of 70 to 110° with respect to the substrate plane.
 8. The drug coating layer according to claim 6, wherein the angle is in the range of 80 to 100° with respect to the substrate plane.
 9. The drug coating layer according to claim 1, wherein the elongated bodies have a length in the direction of the longitudinal axis of 5 to 20 μm.
 10. The drug coating layer according to claim 9, wherein the elongated bodies have a length in the direction of the longitudinal axis of 9 to 11 μm.
 11. The drug coating layer according to claim 1, wherein the elongated bodies have a diameter perpendicular to the longitudinal axis of 0.01 to 5 μm.
 12. The drug coating layer according to claim 11, wherein the elongated bodies have a diameter perpendicular to the longitudinal axis of 0.05 to 4 μm.
 13. The drug coating layer according to claim 11, wherein the elongated bodies have a diameter perpendicular to the longitudinal axis of 0.1 to 3 μm.
 14. A drug coating layer in which flatly elongated hair shaped crystals of a water-insoluble drug are randomly laminated on a substrate surface, wherein longitudinal axes of the crystals partly have a curved portion, and crystals having other shapes are not mixed in the same crystal plane.
 15. The drug coating layer according to claim 14, wherein a surface of the crystal of the water-insoluble drug is further covered with an amorphous film.
 16. The drug coating layer according to claim 14, wherein the flatly elongated hair shaped crystals have a length in a long axis of 10 to 100 μm.
 17. A drug coating layer comprising: a crystalline morphological form of a water-insoluble drug; the drug coating layer comprising crystalline particles of the water-insoluble drug configured to be arranged with regularity on the substrate surface; and excipient particles comprised of an excipient configured to be irregularly arranged between the crystalline particles, wherein a molecular weight of the excipient is less than a molecular weight of the water-insoluble drug, a ratio occupied by the excipient particles per a predetermined area of a substrate is less than a ratio occupied by the crystalline particles, and the excipient particles do not form a matrix.
 18. The drug coating layer according to claim 1, wherein the water-insoluble drug is rapamycin, paclitaxel, docetaxel, or everolimus.
 19. A medical device having the drug coating layer according to claim 1 on the surface of the medical device, wherein the medical device is reduced in diameter to be delivered when delivered into a body, and is enlarged in diameter to release a drug from the drug coating layer at an affected part.
 20. A method for delivering a drug, comprising: delivering the medical device according to claim 19 to a lumen; radially dilating a dilatable portion provided in the medical device; and applying the drug coating layer which the dilatable portion has to the lumen. 